The effect of memantine, an antagonist of the NMDA glutamate receptor, in in vitro and in vivo infections by Trypanosoma cruzi

Abstract

Chagas disease, caused by Trypanosoma cruzi, is a neglected tropical disease that affects 5-6 million people in endemic areas of the Americas. Presently, chemotherapy relies on two compounds that were proposed as trypanocidal drugs four decades ago: nifurtimox and benznidazole. Both drugs are able to eliminate parasitemia and to avoid seroconversion in infected people when used in the acute phase; however, their use in the chronic phase (the time when the majority of cases are diagnosed) is limited due to their serious side effects. Memantine is a glutamate receptor antagonist in the central nervous system of mammals that has been used for the treatment of Alzheimers disease. Our group previously reported memantine as a trypanocidal drug that is able to induce apoptosis-like death in T. cruzi. In the present work, we further investigated the effects of memantine on the infection of RAW 264.7 macrophages in vivo (in BALB/c mice). Here, we showed that memantine is able to diminish NO and Ca2+ entry in both LPS-activated and non-activated cells. These results, together with the fact that memantine was also able to reduce the infection of macrophages, led us to propose that this drug is able to activate a pro-oxidant non-NO-dependent cell defense mechanism. Finally, infected mice that were treated with memantine had diminished parasitemia, cardiac parasitic load, and inflammatory infiltrates. In addition, the treated mice had an increased survival rate. Taken together, these results indicate memantine to be a candidate drug for the treatment of Chagas disease. Author summaryChagas disease affects approximately 5 million people and is caused by the protist parasite Trypanosoma cruzi. Until now, there are no vaccines to prevent the human infection, and the therapy relies on the use of two drugs discovered more than 50 years ago, nifurtimox and benznidazole. Both drugs are efficient during the acute phase of the disease, however their efficacy in the chronic phase, when most of patients are diagnosed is controversial. In addition, both drugs are toxic, causing severe side effects during the treatment. For these reasons, new drugs against T. cruzi are urgently needed. In this work, we report a series of experiments supporting the repositioning of memantine, a drug used for treating Alzheimers disease, to treat the T. cruzi infection in an experimental infection model. Our data show that infected mice treated with memantine have diminished their parasitemia, cardiac parasitic load and inflammatory infiltrates and more importantly, they have diminished their mortality. Taken together, these results prompt memantine as a promising drug for treating Chagas disease.